The pharmaceutical industry is under mounting pressure to reinvent itself due to high failure rates in the clinic and exorbitant research costs. Larger research and development budgets have not yielded the promised increase in medicines entering the marketplace. Clearly new approaches to drug discovery must be explored. In response, Medros was founded on a proprietary platform optimized for high-throughput drug screening in situ by generating human diseases in the fruit fly Drosophila. Our whole organism approach holds the promise of producing higher quality hits with better safety pharmacology and efficacy data than traditional pre-clinical modeling techniques at lower cost. We are establishing a drug discovery platform in which screening is done in Drosophila utilizing a proprietary 96-well format and then verified hits are tested directly in rodent models of disease. Once this in vivo activity is achieved, then whole organism, enzymatic, or cellular assays can be used to further prioritize lead compounds for consideration of IND submission. In this proposal we would like to focus on developing Drosophila as a useful model for mammalian safety pharmacology in order to assess and substantiate our claim that hits emerging from our whole organism screens are of higher quality than can be achieved by current methods. The net result will be an increase in cost efficient leaps from screening to in vivo efficacy, more successful hit-to-IND campaigns, and ultimately safer and more efficacious drugs entering the clinic. At Medros, we wish to bring Drosophila to the same safety and pharmacology standards expected of rodent models. The focus of this Phase I SBIR proposal is to demonstrate that fruit fly pharmacology and toxicology are relevant to mammalian systems and that this understanding will allow for a cost-efficient method to prioritize screening hits for expensive in vivo rodent testing. We will optimize assays to analyze drug concentrations in Drosophila tissue and compare these concentrations to doses from extant fly safety studies as well as rodent safety and pharmacology data. Medros' ultimate vision is to validate an entirely in vivo approach to drug discovery from fly to rodent to man. PUBLIC HEALTH RELEVANCE: New approaches to drug discovery will be required to improve the pharmaceutical industry's success in the clinic and to lower research costs. Medros was founded on a proprietary platform optimized for high- throughput drug screening in the fruit flies Drosophila. Our whole organism approach holds the promise of producing higher quality hits with better safety and efficacy data than traditional pre-clinical modeling techniques at low cost. In this proposal we will focus on understanding Drosophila drug safety and pharmacology in order to substantiate our claim that hits emerging from our whole organism screens are of higher quality than can be achieved by current methods. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]